Bioadhesive Composition With Programmed Release

ABSTRACT

The invention relates to novel viscous liquid compositions for producing pasty forms having a prolonged action and/or release for local applications. These compositions are characterized in that the long-lasting action and/or the prolonged release of the active substance is obtained by the in-situ formation of a matrix film having an increased bioadhesive power and being more or less viscous and biodegradable. The invention also relates to a viscous liquid composition with an increased bioadhesive power for a local application in pasty form with a prolonged release of an active substance, whereby being characterized in that it contains at least one matrix agent, a medium for hydrating the matrix agent, and at least one active substance.

The present invention relates to the pharmaceutical, cosmetic andnutraceutical field and more particularly to that of bio-adhesivesystems with programmed release of active ingredients in the human body.

The human body is constituted by a certain number of cavities accessiblefrom the exterior and covered with mucous membranes. These mucousmembranes are the site of a certain number of diseases or localinfections. This is the case of:

-   -   the oral mucous membrane, which extends from the mouth to the        esophagus by passing via the throat;    -   the nasal mucous membrane, which extends from the nose to the        rear throat    -   the rectal mucous membrane covering the distal part of the large        intestine    -   the vaginal mucous membrane    -   the ocular mucous membrane called the cornea.

These mucous membranes have the characteristic of being permanentlymoistened by liquids specific to the mucous membrane in question.

These secretions have two major roles concerning the mucous membrane:

-   -   a role of protection for the latter vis-à-vis external stresses    -   a role as lubricant.

It is thus in the case of lachrymal liquid, saliva, and vaginalsecretions.

The accessibility of these mucous membranes via the exterior allowstherefore a treatment known as local if necessary.

In fact, a certain number of products exist to treat local infectionssuch as:

-   -   suckable tablets for the treatments of mouth ulcers, stomatitis,        gingivitis, glossitis, etc. . . .    -   gels and creams for oral, vaginal, and rectal (hemorrhoids), and        ocular treatments,    -   liquids for the nasal route (nasal solutes) and for the ocular        route (eye lotions).

However these products have a very short action duration from atherapeutic standpoint because of a perpetual “washing” of these mucousmembranes by the secretions thus eliminating the active ingredientdeposited in situ.

This thus requires repeated local administrations that in certain casesare not very agreeable for the patient. By way of example, we can citethe repeated administrations of eye lotion.

Furthermore, to ensure the remission of the infection, the localtreatment is generally coupled with a systemic treatment.

By “systemic treatment” we mean the supply via the blood of an activeingredient to the inside of the entire organism. This supply can becarried out by direct administration in blood circulation (intravenousadministration) or by oral administration.

As an example of a local treatment coupled with a systemic treatment, wecan cite the case to acyclovir, active ingredient used in the treatmentof herpes.

Herpes is caused by a virus that develops at the oral, vaginal andocular area.

This affection is treated locally by creams. According to theseriousness of the affection, the local treatment is coupled with asystemic treatment. It is also thus for an ocular herpes. Localtreatment requires 5 applications per day in the conjunctival cul-de-sacof the eye. The pulse therapy in the case of vaginal herpes isidentical. In several cases of the two impairments, an oraladministration (systemic administration) is coupled with the localtreatment.

Thus it appears necessary, for the comfort of the patient, to havesystems that make it possible to maintain a local action duration moresubstantial than simple creams, in order to reduce the number ofapplications per day.

Broadly speaking, any system that makes it possible to prolong theaction of the active ingredient in the organism is called “form withprolonged or programmed release”.

To date such systems have been for the most part developed for the oralroute. They are generally tablets or gelatin capsules containingmicrogranules. These forms with prolonged release or known as programmedare numerous and belong to different categories according to theexcipients used to slow down the release of the active ingredients. Theyare:

-   -   matrix forms. They are generally tablets from which the active        ingredient is released, either        -   by erosion of the support, or        -   by diffusion through the network formed by the ingredients            of the tablet    -   coated forms. They are conventional tablets or microgranules,        having undergone a coating with the aid of substances having        certain properties enabling a slow liberation through the formed        membrane.

Numerous patents have been awarded in this field and are related to theactive ingredients used in this form.

Apart from the oral route few systems having prolonged release have beendeveloped.

For the intravenous route, this type of system does not exist.

In the case of the intramuscular route, the prolongation of the actionis obtained by injection of a suspension of particles intended to besolubilized gradually in the organism. The best-known example is that ofinsulin: intramuscular injection of particles of insulin for a 24 hoursaction minimum.

A second example is that of the administration of implants in the caseof hormone therapy: deposit of small hormone (progestins) tablets underthe skin that are intended to dissolve slowly.

Concerning the cutaneous route, a system with prolonged release has beendeveloped for a systemic administration of active ingredients: they arethe transdermal systems known as “patch”.

The best-known example is the nicotine patch for the weaning of smokers.

From the local standpoint, very few things exist.

The route that has received great attention in this field is the ocularroute.

A certain number of products have been developed such as:

-   -   soluble gels that slow down the release of the active ingredient        because of their elevated viscosity. The viscosity prolongs the        contact time of the active ingredient in the cornea and presence        time in the conjunctival cul-de-sac. This intensification of the        action is due to the slowing down of the elimination process in        the lachrymal channel, due to the viscosity of the product.

These gels are generally based on water-soluble polymeric molecules suchas polyvinyl alcohol, cellulose derivatives, and acrylic derivatives.

By way of example can be cited the works of:

-   -   WANG and HAMMARLUNG (1) on gels of polyvinyl alcohol and of        hydroxypropylmethyl cellulose containing homatropine hypobromite        having a myotic effect    -   HAAS and Coll. (2) on methylcellulose gels containing        pilocarpine    -   GOLBERG and Coll. (3) as well as those of MANDELL and Coll. (4)        and MARCH and Coll. (5) on high viscosity acrylic gels        containing pilocarpine hydrochlorate    -   SCHOENWALD and Coll. (6) on Carbopol® gels containing        prednisolone acetate

Other polymers can be used with the aim of delaying the release of theactive ingredient such as alginic acid (Carteol® LP), and gellane gums(Timoptol®).

In certain cases, a certain bio-adhesion of the materials used wouldhave been displayed, in the cornea. It could be the case of Carbopol®(HO-WAH HUI and Coll. [7]). But the bio-adhesion mechanism could not beperfectly established.

-   -   emulsions or pseudo-latex. They are emulsions containing        microballs based on cellulose acetophtalate or others such as        polymetacrylic derivatives, on which the active ingredient is        fixed. These suspended particles deposit themselves in the        conjunctival cul-de-sac and gradually liberate the active        ingredient.    -   Inserts such as:    -   pre-cast hydrophilic matrices or hydrophilic lenses, which are        considered as reservoirs because they are capable of being        hydrated to nearly 85%. However the re-release of active        ingredient contained in this reservoir is rapid    -   erodable soluble implants impregnated with active ingredients        (oval plates or pellets). Placed in the conjunctival cul-de-sac,        they saturate quickly with lachrymal liquid. The liberation of        the active ingredient is done by progressive dissolution of the        support. A concrete example of this system is the        hydroxypropylcellulose-based product Lacrisert®.

In the present case, the emulsions or pseudo-latexes as well as theinserts, are not defined as bio-adhesive systems with prolonged release.Their prolonged activity comes from the fact they are maintained inplace in the eye in the conjunctival cul-de-sac, which plays in thiscase the role of storing active ingredients. In this situation, nophysical or chemical combination is used with one of the biologicalcomponents of the eye.

Concerning the nasal mucous membrane few things have been exploredbecause of the secondary effects that can be brought about by theapplication of substances which, generally in the case of the forms withprolonged action, are products:

-   -   insoluble in aqueous medium such as celluloses;    -   presenting viscosities non compatible with those of the        organism.

Thus, a risk of passage of these substances in the respiratory tracts,having a potential for leading to an obstruction of the bronchi andbronchioles, is to be feared.

However studies have been conducted with Carbopol® (NAGAI and Coll. [8]and CHU and Coll. [9])). The bioavailability of the active ingredientswould be augmented when administrated in the state:

-   -   of powders: active ingredient/Carbopol® mixture    -   and of hydrogels.

The American patent U.S. Pat. No. 4,226,848 refers to use of cellulosederivatives and acrylic polymers for a bio-adhesive nasal application.

Contrary to the ocular route or to the nasal route where in most casesthe bio-adhesive preparations are introduced in the form of gel orcreams. The forms known as bio-adhesives for the oral route could bemostly introduced in the form of tablets or patches. The ingredientsknown as bio-adhesives tested within this application framework are:

-   -   Carbopol®    -   hydroxypropylmethylcellulose    -   chitosan    -   and gum of acacia.

Some pasty forms exist, of which the principal bio-adhesive excipientsused are:

-   -   cellulose derivatives, carboxymethylcellulose among others    -   very high purity glycerides that have the property of gelifying        in contact with saliva    -   and Carbopol®

However even if the tablets and the patches ensure a prolonged releaseof the active ingredient in the oral cavity, the maintenance during 8hours of such a form in the mouth is not conceivable for a patient.Furthermore, the pasty forms do not resist the “washing” action of themucous membrane by the saliva and thus are not maintained in situ on an8 hours period.

In the case of the vaginal route the useable forms are identical tothose of the oral route:

-   -   tablets    -   pasty forms

As previously the tablets can very well offer a prolonged release insitu.

However the administration of such a form is not practical for thepatient and a rejection may occur after a certain time.

In the case of the pasty forms we find the same bio-adhesive excipientsas for the oral or ocular route. However, as for the oral route, thevaginal secretions do not allow the maintenance in place of suchpreparations for a long action duration.

Apart from suppositories, the forms applied locally in the rectal areaare generally creams or gels for the treatment of hemorrhoids. Thisroute can also be used with the aim of a systemic action of the activeingredients which, administered by oral route, are quickly degradedhepatically. The rectal route avoids this problem.

To date very few forms with prolonged release have been developed forthis route. Work has been realized by HOSNY and coll. (10) using, asbio-adhesive agent, Carbopol® for the rectal administration ofindomethacine.

Thus, after a thorough study of the literature in the field of the formswith prolonged release, it has been unable to be demonstrated aneffective solution for obtaining a form with prolonged release of longduration, greater than 2 hours, because of the phenomenon of washing ofthe mucous membranes by the local secretions.

Given this situation and to remedy it, the invention offers an originalconcept of viscous liquid compositions intended for the realization ofpasty forms having prolonged action and/or release for localapplications. These compositions are characterized in that long lastingand/or prolonged action and/or release of the active ingredient isobtained by the in situ formation of a matrix film having reinforcedbio-adhesive capacity, more or less viscous and biodegradable. Theaforementioned reinforced bio-adhesive character is obtained by acomplexation reaction of the matrix agent with one of the components ofthe local secretions or of the mucous membrane, leading, under theeffect of a permanent washing of the mucous membranes by the secretions,to an action and/or release, on a period greater than 2 hours, of theactive ingredient previously dissolved or dispersed with the aid of asolvent, this action and/or release being changeable by incorporation ofappropriate additives.

Thus, the purpose of the present invention is to realize in situ, afterapplication of the preparation, a matrix film having reinforced andbiodegradable bio-adhesive capacity, of which the action and/or releaseof the active ingredient is, as far as possible, independent of the pHand/or independent of the action of the secretions of the mucousmembranes, depending on the excipients used to reinforce the solidity ofthe aforesaid bio-adhesive matrix film.

The reinforced bio-adhesion is such that it is quasi-instantaneous fromthe moment of application on the mucous membranes.

By “bio-adhesion” we mean the capacity that a biological or syntheticsubstance has to “stick” to a biological or mucous membrane.

By “reinforced” we mean the creation of supplemental bonds with thesupport represented by the mucous membrane, other than those observedwith the conventional bio-adhesive excipients.

By “matrix film” we mean the formation of a three-dimensional network,more or less solid, more or less thick, and more or less porous, inwhich is included the active substance.

By “biodegradable” we mean the degradation of a support generated by abiological mechanism such as the action of enzymes but also by amechanical erosion mechanism due to the “washing” secretions of theorganism.

By “washing” we mean a repeated passage of a solution on the samesupport until total exhaustion of the latter.

This invention is applicable to the preparations intended for the oralmucous membrane, as well as the nasal, vaginal and rectal mucousmembranes; and the cornea.

This invention is based on the fact that certain substances in the solidstate or the liquid state have the property to complex with certainmolecules of the mucous membranes when they are applied to the latter.Thus there is attachment of the matrix agent to the surface of themucous membranes thus forming a three-dimensional network from which theaction and/or from which the active ingredient diffuses gradually overtime. The substances used are mostly materials of natural origin muchused in the pharmaceutical, cosmetic and dietetic field.

By “complex” we mean the formation of a chemical bond other than thehydrogen bonds encountered with the majority of the other agents knownas bio-adhesives. This bond is characterized in that energy isintermediate between the energy of a covalent bond and the energy of ahydrogen bond thus leading to a structure more resistant to thephenomenon of “washing”.

Thus, the invention has as the aim a viscous liquid composition withreinforced bio-adhesive capacity, for a local application in pasty formhaving prolonged release of an active ingredient, characterized in thatit includes at least a matrix agent, a hydration medium of matrix agentand at least one active ingredient.

Obtaining of the aforesaid bio-adhesive matrix films having prolongedrelease being the subject of the present invention calls for substancesknown as matrix agents, which, in contact with the mucous membranes,offer a reinforced bio-adhesive capacity.

These substances can be used alone and create a viscous film or a moreor less solid structure, in which the active ingredient(s) are dissolvedor dispersed.

These same substances can be used in combination with other excipientswith the aim of reinforcing the structure of the aforesaid matrix filmand their bio-adhesive property.

In combination with other excipients, these matrix agents play the roleof “binder”.

By “binder” we mean substances acting as cements between the particlesof a network with the aim of reinforcing a more or less solid structure.

Thus, these matrix substances avoid the dispersion of the otherexcipients within the secretions of the organism by their imprisonmentin the viscous gangue or the spongy structure formed at the surface ofthe mucous membrane.

As a result, depending on the solidity of the obtained matrix film, theaction of the aforesaid film or the release of an active ingredientincluded in such a system can vary between 1 to 48 hours according tothe action site of the aforementioned preparation.

Preferably according to the invention, the release time of the activeingredient is between 2 and 12 hours for the oral, nasal, and ocularadministration and the release time of the active ingredient is greaterthan 12 hours for vaginal administration.

Matrix agents allowing attainment the aforementioned films and playingthe role of “binder” belong to the class of the natural polymers,polysaccharides:

The polysaccharides retained within the framework of this invention arethe carrageenans.

The carrageenans have been known for more than 600 years in the medicalfield and in the nutritional field in particular for their originalproperty, which consists of gelifying milk by simply heating it.

They are polysaccharides, polymers of galactose more or less sulfated.

The carrageenans are extracted from different algae: Chondrus crispus,Gigartina stellata, Gigartina acicularis, Gigartina skottsbergii,Gigartina pistillata, Gigartina chamissoi, Iridea, Eucheuma cottoni,Eucheuma spinosum.

The extraction process used lead to different types of carrageenans thebasic skeleton of which is a chain of D-galactose residues alternativelybonded at α-(I-3) and β-(I-4).

The different qualities are due to the quantity and the position of thesulphate groups and to the presence or not of 3,6 anhydro bridge ongalactose bonded at 1 and 4.

The proportion of the different sulphates groups and theanhydrogalactose bridge at 3,6 allowed isolation of different types ofcarrageenans. They are the iota-, kappa-, lambda-, beta-, nu-, andmu-carrageenans.

The lambda-forms exhibit many sulfurated groups compared to thekappa-forms. The iota-forms are intermediate.

The mu- and nu-forms are in lesser quantities and are considered asimpurities decreasing the gelifying effect of the iota- and kappa-forms.

The types of carrageenans retained for the present invention are thelambda- and the iota-carrageenans.

Compared to the kappa-carrageenans, the lambda- and theiota-carrageenans offer no syneresis phenomenon.

Lambda-carrageenans offer no gelifying properties, but thickening.

In the case of the iota-carrageenans, the gelifying property developsonly if the preparation is subjected to heat.

Whether it be the iota- or the lambda-carrageenans, they are hygroscopichydrocolloid substances.

Resulting from the contact with the mucous membranes, these substanceswill have the possibility of developing bio-adhesive properties like theconventional excipients bio-adhesive such as Carbopol® orcarboxymethylcellulose defined as polymers suitable for forming more orless solid three-dimensional networks also.

The conventional bio-adhesive mechanism of the excipients known asbio-adhesives is defined as being an interaction of the aforesaidexcipient with mucus covering the mucous membranes of the organism. Thismucus is generally highly hydrated and offers a certain viscosity due tothe presence of a glycoproteine, mucin.

According to their chemical nature, high molecular weight polymers,these excipients known as bio-adhesives are hygroscopic. Thus, incontact with the mucous membranes, these polymers expand quickly withthe formation of hydrogen bonds between the hydrophilic groups of thepolymer and those of the mucus and inter alia those of the mucin.Consequently there is formation of a three-dimensional network from apolymer/mucin interaction.

However, the hydrogen bonds are bonds of weak energy. Consequently adilution of the medium or the constant “washing” of a support will leadto a rapid breaking of these bonds thus decreasing the bio-adhesivecharacter of these excipients.

On the other hand, in the case of iota- and lambda-carrageenans, thebio-adhesive character is known as “reinforced” because besides thecreation of the hydrogen bonds observed with the conventionalexcipients, other bonds are formed with the support.

In fact, it has been noted that the iota- and lambda-carrageenanspossess sulphate groups on the skeleton of the molecule. These chemicalgroups are very reactive and create complexing reactions with certainmolecules having free protons on some of their atoms such as nitrogenand sulphur. Because of the presence of these free protons, N²⁺ or S⁴⁺,anionic groups, such as the sulphate groups of the carrageenans, SO₄ ²⁻,react very strongly with these molecules.

Thus, the iota- and lambda-carrageenans in contact with mucin and of themucous membrane, having in both cases nitrogen atoms, will create athree-dimensional network constituted:

-   -   by hydrogen bonds formed between the OH groups of polysaccharide        and those of mucin and the water present in mucus    -   by complexation bonds between the sulphate groups of        polysaccharide and the nitrogen atoms of mucin and the mucous        membrane.

The “reinforced” bio-adhesive character has been revealed by acomparative study between Carbopol®934P NF and the lambda-carrageenans(Benvisco® LPB 2301).

The study is based on the realization of 2 solutions having a definedviscosity of 3000 mPa.

The viscosity of the solution was not chosen arbitrarily but accordingto the final mechanical properties of the solution: easily diffusiblesolution (sprayable).

Thus, for a viscosity of 3000 cPs, the concentrations in agentsbio-adhesives are:

-   -   2.0% for the lambda-carrageenans.    -   0.6% for Carbopol®

Beyond these values, the products obtained no longer display theappearance of viscous solutions, but of gels.

Contrary to all the studies carried out on the bio-adhesivity using astainless steel support, the studies of the bio-adhesivity of thesesolutions has been carried out on biological cellulose membrane (osmoticmembrane) impregnated with a solution of mucin to 5% in a pH 6.8phosphate buffer.

The impregnation of the membrane is effectuated in the 30 seconds beforethe deposit of the solutions.

The impregnation of the membrane is such that a liquid film is formed atthe surface of the latter thus simulating what occurs in the area of thedifferent mucous: wetness of the mucous membranes.

0.5 ml of solution to be tested is deposited at the surface of thisimpregnated membrane, at 6 cm from the inferior edge.

The “reinforced” character of the bio-adhesivity is tested by “washing”the deposit with a pH 6.8 buffered medium simulating the differentsecretions of the organism.

The “washing” of these deposits is carried out by using the tabletdisintegration apparatus described in Pharmacopee Europeenne, 4^(th)edition.

This apparatus sketches out a back and forth movement from top to bottomat the ratio of 30 per minute and with an amplitude of 12 cm.

The impregnated membrane is attached to a rigid support (glass plate),itself vertically attached to the lever drawing out the back and forthmovement.

The disintegration apparatus as well as a chronometer are activated whenthe deposit surplus begins to drain to the inferior part of themembrane.

Besides the comparative study conducted between Carbopol® and thelambda-carrageenans impregnated on membrane, a parallel study has beencarried out on a simply moistened membrane.

By “simply moistened” we mean the absence of an aqueous film at thesurface of the membrane.

Contrary to all expectations, lambda-carrageenans in contact with liquidfilm at the surface of the biological membrane offer a contact timedefinitely more substantial than Carbopol® placed under the sameconditions.

A significant difference of 2 minutes 36 seconds (2′36″) is observed inthe case of Carbopol®, between contact times on simply moist membraneand impregnated membrane against a nonsignificant difference of 1 minute45 seconds (1′45″) for the lambda-carrageenans.

Wet membrane Impregnated Membrane Lambda-carrageenans 9′43″ ^(±) 0′47″8′52″ ^(±) 0′16″ Carbopol ® 9′29″ ± 0′43″ 6′52″ ^(±) 0′9″ 

This difference of behavior is all the more significant because thecarrageenans have a rheology totally different from that of Carbopol®.

In fact, the liquid-based carrageenan preparations are characterized asNewtonian products that is to say that they flow freely under the effectof only their mass, which is not the case of Carbopol

Furthermore, these same products are also characterized as thixotropicsolutions, that is to say that these aforementioned solutions, havingthe appearance of a solid at rest, liquefy rapidly, under the effect ofan agitation. This property is not observed with Carbopol.

Thus, after deposit of the carrageenans solution at the surface of thewet membrane, this flow has been clearly observed from the moment ofplacement in vertical position of the support and continues from themoment of activation of the apparatus. On the other hand, in the case ofCarbopol®, this flow was clearly less pronounced after activation of theapparatus.

However, contrary to all expectations, on impregnated membrane, themobile liquid film at the surface of the membrane, free of all flow invertical position, saw its flow impeded by the presence of thecarrageenans at its surface. Contrary to the results observed on the wetmembrane, the flow of the deposit is practically nonexistent when theapparatus is activated.

In the case of Carbopol®, an opposite result is observed. The liquidfilm at the surface of the membrane is not impeded in its flow thusdriving the effectuated deposit with it.

This bio-adhesive property has also been demonstrated by the recordingof the flow times of a carrageenan-based solution on a 45°-inclinedplane covered with the same biological membrane impregnated or notimpregnated with mucin. Significant time differences have been notedbetween the flow on non-impregnated membrane and impregnated membrane.

Aptitude to Bio-adhesivity Concentration the adhesion factor in WithoutWith F_(aa) F_(ba) carrageenans mucin mucin Data Mean Data Means 2% 38″54″ 16″ 12″ 1.42 1.31 43″ 52″ 9″ ±3″ 1.21 ±0.11 41″ 53′′′ 12″ 28.47%1.29 8.11% 3%  5′52  7′58 126″ 122″  1.36 1.34  5′59  8′01 122″ ±3″ 1.34±0.02  6′03  8′02 119″ 2.87″   1.33 1.13% 5% 17′58 22′05 247″ 251″  1.231.23 17′59 22′14 255″ ±4″ 1.24 ±0.005 18′08 22′19 251″  1.59% 1.23 0.47%

Despite the carrageenans being the object of a certain number of patentsin more diverse fields other than pharmaceuticals, cosmetics, anddietetics, they are, however, seldom used in the realization of formshaving prolonged release and even less for the realization ofbio-adhesive systems having prolonged release.

In fact, in the field of forms having prolonged release we can citeinter alia, international application WO 03101424 mentioningcarrageenans for the realization of matrices having prolonged release insolid form.

In the case of U.S. Pat. No. 6,355,272, the carrageenans are complexedwith the active ingredient, which is gradually released over time in thedigestive tract.

Similarly international application WO 0100177 shields theamoxicycline/carrageenans combination for a prolonged release of theantibiotic.

Hercules in his U.S. Pat. No. 6,358,525 shields differenthydroxypropylcellulose and hydrocolloid based compositions such as thecarrageenans, in order to slow down the availability of the activesubstances to the organism.

The patent application US2004019010 uses the carrageenan gels assubstitute for the vitreous humour of the eye during ocular surgeries,such as cataract. The vitreous humour is replaced by these gels which,gradually over time, see their viscosity diminished to avoid anexcessively strong intra-ocular pressure. These gels can be combinedwith active substances such as anti-inflammatory drugs, antibiotics,etc, which thus avoid any post-operative complications.

U.S. Pat. No. 5,403,841 shields carrageenans for the ophthalmicapplication of certain active ingredients. In the present case, abio-adhesion of the carrageenans is not claimed but, instead, aquasi-instantaneous increase of the viscosity carrageenan-based solutioninstilled in the eye.

Likewise patent EP424043 clearly refers to the use of the carrageenansto increase the release time of the ingredients in the eye. This resultwould be due to an increase in the viscosity of the lachrymal liquid byinteraction of the carrageenans with the proteins of the tears, thelysozymes among others. In no case is the interaction process described.In fact no mention is made:

-   -   of creation of hydrogen bonds    -   of complexing reaction    -   of precipitation reaction, which can also be an augmentation        mechanism of the bioavailability by formation of in situ        microcrystals.

Furthermore there is absolutely no mention made of a bio-adhesiveactivity of these preparations in the cornea, the exterior layer ofwhich is covered with a mixture of lipids and mucin.

Regarding the oral area, it is made mention in U.S. Pat. No. 5,672,356of the use of the carrageenans as gelling agent delaying the release ofthe active ingredient, the bio-adhesion being supplied by the copolymerof methylvinyl ether and maleic anhydride.

Regarding the esophagus, U.S. Pat. No. 6,610,667 shields a compositionof which the principal agent of bio-adhesion is alginate and has alesser degree of other hydrocolloids such as the xanthan gum,galactomananes, glucomananes and carrageenans. The application is mainlycentered around the combination alginate/gum xanthane oralginate/galactomananes or glucomananes. Furthermore, the esophagus isfar from being a cavity of easy access from the exterior.

The international application WO2004/075920 uses the carrageenans asvector of active ingredients in the pulmonary area with the aim ofdelaying their release. Here also, the lungs are far from beingconsidered as a cavity in the same fashion as the oral, vaginal, orrectal, cavity therefore far from being easily accessible from theexterior. Furthermore, the pulmonary secretions are definitely lesssubstantial than those observed to exit from the salivary or lachrymalglands.

Other patents such as patent EP1452168 concern cutaneous applications ofthe carrageenans. The patent application US2002071861 makes use of thecarrageenans but the bio-adhesive aspect of these preparations issupplied by carboxymethylcellulose, hydroxypropylmethylcellulose andCarbopol®.

Finally, the patents U.S. Pat. No. 6,159,491, U.S. Pat. No. 5,069,906and U.S. Pat. No. 4,983,393 refer to the use of the carrageenans inprolonged release systems intended for vaginal administration.

U.S. Pat. No. 6,159,491 makes use of a combination of Carbopol®(Polycarbophil®) with carrageenans and agarose of high purity with theaim of having a release twice. In the present case the carrageenans areused as gellants, delaying the release of the active substances andCarbopol® as bio-adhesive.

U.S. Pat. No. 5,069,906 and U.S. Pat. No. 4,983,393 shield thecarrageenans only as a matrix agent delaying the release of the actives.The bio-adhesive character is not mentioned.

In the present invention, according to the zone treated, theconcentration in matrix agent, especially carrageenans, in the mediumvaries from 0.5% to 30% in relation to the final mass of thepreparation.

The hydrating solvent of the matrix agent, especially carrageenans, canbe aqueous or hydro-alcoholic. The proportion of the alcoholic phase canvary from 10% to 90% in mass in relation to the total volume of thehydrating phase.

The alcoholic phase can be embodied by ethylic alcohol and isopropylalcohol.

The addition of certain ions can enable a better hydration of thecarrageenans and at the same time enable augmentation of theirconcentration in the medium.

The agents supporting this hydration belong to the class of alkalinesand the alkaline-earths. They are inter alia:

-   -   sodium and potassium salts of hydrochloric, sulphuric, nitric,        phosphoric, citric acids and derivatives,    -   and potassium and sodium hydroxides.

The proportion of alkaline and alkaline-earth ions introducible into themedium varies between 0% to 50% in mass in relation to the total mass ofthe preparation.

The aqueous phase used can be buffered to support the stability of theactive substances but also the stability of the matrix agent.

In fact, the carrageenans in the presence of dextrose, in neutralmedium, undergo progressive hydrolysis in time, increased by the actionof heat.

It is thus that in neutral medium and on a 24 hour period one observes areduction in the viscosity of the product by a progressive hydrolysis ofthe carrageenans releasing acid radicals in the medium.

Within the acid framework of buffer solutions, the compositions can beas follows:

-   -   sodium hydrochloric/chloride acid or potassium        hydrochloric/phtalate acid or hydrochloric/glycocolle acid        buffer.    -   citric acid/citrate or citric acid/sodium hydroxide buffer    -   lactic acid/lactate buffer.

The proportion of the different components make it possible to maintainan acid pH ranging between 2 and 5.

In the case of the carrageenans a better stability is observed inneutral or basic medium.

The buffer solutions that can be thus used respond to the followingcompositions:

-   -   phosphates buffer: sodium or potassium phosphate    -   carbonates buffer: bicarbonate/carbonate    -   phthalate buffer: potassium/hydrochloric acid diphthalate    -   borates buffer: boric acid/sodium borate

The value of the pH of the buffered medium can vary from 5 to 12.

The present invention is intended for the administration of a certainnumber of active substances.

The active substances that can be in such a form belong to certainpharmacological categories, namely analgesics, anti-inflammatoriesantispasmodics, cytotoxics, antibiotics, antifungals, disinfectants,pesticides, hormones, antivirals, antimigraine agents, anti-allergics,analeptics, respiratory agents, spermicides, anti-hemmorrhoidal agents,vasoconstrictors, vasodilators, antipruritics, uterorelaxants,antiglaucoma agents, mydriatics, antiasthmatics.

These substances can be incorporated in the dissolved state in theaqueous or hydro-alcoholic phase of the preparation subject to thepresent invention or in the solid state dispersed in the matrix film.

Despite that a certain number of these substances can be solubilized inthe hydration medium of the carrageenans, others require asolubilization in an organic phase.

Among organic solvents usable without danger to the human organism areretained:

-   -   vegetable oils, hydrogenated vegetable oils, ethoxylated        vegetable oils: olive oil, hazel nut oil, coconut oil, castor        oil, soy oil, sesame oil, etc.    -   mineral oils: paraffin, isoparaffin, cycloparaffin, silicone        oils, isohexadecane, isododecane, and derivatives, etc    -   natural oils, squalane, hexamethyltetracosane, the mono-, di-        and triglycerides, etc.    -   synthetic oils: polyisobutene, hydrogenated polyisobutene, etc.    -   and other solvents: ethanol, propanol-1, propanol-2,        polypropylene, propylene carbonate, dimethyl isosorbide ether,        polyoxyethylene glycols (Macrogols), glycerol, fatty acid esters        of polyethylene, fatty acid esters of propylene glycol,        dicaprylate/dicaprate esters of propylene glycol,        caprylate/caprate esters of glycerol, fatty acid esters of        polyoxyethylene/polyoxypropylene glycol, triacetin, isopropyl        myristate, glycofurol, liquid fatty acid esters, ethyl acetate,        butanol, propylene glycol acetate, butyl acetate, ethylene        glycol monobutyl ether, ethyl lactate, butyl acetate, diethylene        glycol-monoethyl ether, glycerin monooleate, glycerin linoleate,        fatty acid glycerol esters, fatty acid esters of glycerol and        PEG etc.

The proportion of these different solvents, used in these preparations,depends on the solubility of the active ingredients and can vary from 1%to 50% in volume in relation to the total volume of the hydrating phase.

In certain cases, these solvents require the use of surface-activeagents to avoid any phase separation between the hydrating phase and theorganic solution of actives.

The surface-active agents usable in the present invention are:

-   -   nonionic surface-active agents:    -   sorbitan esters: polysorbates, Spans, Tweens, etc. . . .    -   polyethoxylated fatty acids: stearate of PEG-8 stearate through        stearate of PEG-100;    -   polyethoxylated fatty alcohols: mixtures of monolaurate ethers        of PEG having from 4 to 23 oxyethylene groups in the        polyoxyethylene chain, etc. . . .    -   glycol esters: methylglycol stearate;    -   glycerol esters: glycerol monostearate, PEG-75 stearate, glycol        and PEG 6-32 stearate, etc. . . .    -   PEG esters;    -   saccharose esters;    -   fatty alcohol and PEG ethers: Brij;    -   ethers of alkylphenols and PEG;    -   surface-active agents having an amid function:    -   monoethanol amides of coprah fatty acids, monoethanol amide of        lauric acid, etc. . . .    -   diethanolamide of myristic acid, of lauric acid, etc. . . .    -   monoisopropanolamide of lauric acid.    -   phospholipids, such as phosphatidylcholine, phosphatidylserine,    -   the ionic surface-active agents:    -   sulphate derivatives: sodium laurylsulfate and its derivatives;    -   sulphonated derivatives: sodium dodecylsulfosuccinate and its        derivatives;    -   quaternary ammonium compounds: cetyltrimethylammonium chloride;        lauryl pyridium chloride, distearyldimethylammonium chloride,        etc. . . .    -   amphoterics: coprah alkyldimethylammonium betaines, fatty acid        amides with betaines, lauryl-α-iminodiproprionic acid and its        derivatives, lauryl-myristyl-α-aminoproprionic acid and its        derivatives, etc. . . .

Furthermore the surface-active agents can be used to reinforce thebio-adhesive properties of the carrageenans, among them thephospholipides such as the phosphatidylcholine.

Based on the same tests as previously the phosphatidylcholine increasesthe bio-adhesive capacity of the carrageenans in a significant manner.For a same viscosity and a lesser concentration the difference of flowtime on impregnated membrane and on non-impregnated membrane is on theorder of 414 seconds. In the absence of phospholipides this differenceis only 122 seconds

Aptitude to Bio-adhesivity Concentration the adhesion factor in WithoutWith F_(aa) F_(ba) Viscosity carrageenans mucin mucin Data Mean DataMeans 2533 cPs 2% + phospholipides 9′38 17′11 453″ 414″ 1.78 1.72 9′5415′31 337″ ±67″ 1.56 ±0.14 9′12 16′46 454″ 16.22% 1.82 8.13% 2625 cPs 3%5′52  7′58 126″ 122″ 1.36 1.34 5′59  8′01 122″  ±3″ 1.34 ±0.02 6′03 8′02 119″  2.87% 1.33 1.13%

The quantity of these substances used to promote the solubilization orthe dispersion of the active ingredients as well as increase thebio-adhesive capacity of the carrageenans can vary from 0 to 50% inweight in relation to the total mass of the excipients.

Besides the fact that the active ingredients can be solubilized in thehydrating phase or in another solvent, these can also be incorporated inthe solid state creating a bio-adhesive suspension.

As a result the active ingredients must satisfy a particle sizecriterion.

Thus the granulometric distribution of the powders can spread from 1 μmto 1000 μm, preferably ranging between 1 μm and 250 μm.

As was demonstrated during a certain number of trials, the carrageenanscreated a viscous film, of gelatinous appearance and of soft to firmconsistency according to the concentration.

A reinforcement of this structure can be effectuated by introductioninto the medium substances that, with contact with the secretions, aregoing to increase the solidity of this network.

Many substances can play this role. But only the starches have beenretained, in particular their derivatives, because they are productsthat are more or less soluble in the hydration medium that reinforce thematrix structure of the carrageenans with the aid of their aptitude toform viscous networks in contact with the water.

Thus the native starches are retained as structuring agents in theaforementioned invention as well as their derivative products resultingfrom:

-   -   physical modifications: pre-gelatinization    -   chemical modifications:    -   chemical or enzymatic dextrinisation reaction    -   acid hydrolysis    -   oxidation reaction    -   substitution reaction by:    -   phosphoric acid    -   adipic acid    -   acetic acid    -   hydroxypropyl or hydroxyethyl groups.

These different structuring agents can be obtained from starches ofwheat, rice, corn, manioc and potato.

The quantities used in order to obtain an action and/or a release of theactive ingredient between 2 and 48 hours can vary from 0 to 50% in massin relation to the total mass of the preparation

An important factor to rapidly obtain a compact structure, is the sizeof the particles of these aforesaid substances. Because the finer theparticles, the more substantial the expansion capacity and the greaterthe density of the network formed (fewer inter-particle interstices).

Thus the particle size of the starches and modified starches making suchresults attainable must range between 1 μm and 1000 μm with a preferencefor a size ranging between 1 μm and 100 μm.

Preservation additives and dyes can be introduced into the composition.

The proportion of preservative can vary from 0% to 10% in mass inrelation to the total mass of the preparation.

The dyes can be water-soluble or fixed on alumina lacquer or anothersupport.

The optimum percentage of required dye ranges between 0.01% and 5% inmass in relation to the total mass of the preparation.

In the case of preparations intended for the oral cavity, moisteningproducts can be added to the bio-adhesive medium.

By “moistening” we mean substances that bring a certain moisture to themedium in which they are present by way of their intrinsic hygroscopicproperties, namely fixation of the moisture of the surroundingatmosphere moisture.

These products have the characteristic of facilitating the hydration ofthe carrageenans, which is realized by an increase in the bio-adhesivityof the latter.

Thus based on the same tests as previously, it appears that theglycerin, for an identical concentration in carrageenans, leads to aflow time on the membrane impregnated with mucin, clearly greater than asimple aqueous preparation of carrageenans.

In fact, at a flow distance of 10 cm, the preparation does not reachthis distance after 60 minutes of deposit because of a strong reactionwith the support

Aptitude to Bio-adhesivity Concentration the adhesion factor in WithoutF_(aa) F_(ba) carrageenans mucin With mucin Data Mean Data Mean 3% +glycerine 36′42 8.4 cm in 60′ / 15400 cPs 36′35 8.7 cm in 60′ / / / /36′33 8.2 cm in 60′ / 3%  5′52 7′58 126″ 122″ 1.36 1.34  5′59 8′01 122″ ±3″ 1.34 ±0.02  6′03 8′02 119″ 2.87% 1.33 1.13%

Along a distance of 7.5 cm, it appears clearly that the difference inflow between the two preparations is definitely significant. The factorof bio-adhesiveness, which is nothing other than the relationshipbetween the flow time of the preparation with mucin over the flow timewithout mucin, is definitely higher than the one with carrageenans aloneregarding a same concentration in carrageenans that this is for anidentical concentration in carrageenans or an identical viscosity of themedium.

Aptitude to Bio-adhesivity Concentration the adhesion Factor in WithoutWith F_(aa) F_(ba) carrageenans mucin mucin Data Mean Data Mean 3% +glycerine 23′05 49′02 1557″ 1548″  2.12 2.11 15400 cPs 23′10 48′56 1546″±7″ 2.11 ±0.01 23′15 48′58 1543   0.47% 2.10 0.47% 3%  1′43  2′32  49″44″ 1.47 1.45  2625 cPs  1′38  2′24  46″ ±5″ 1.47 ±0.04  1′45  2′13  38″12.82%  1.40 2.79% 10′01 13′49  228″ 219″  1.38 1.38 5% 10′13 13′39 206″ ±11″  1.37 ±0.005 15933 cPs  9′44 13′28  224″ 5.34% 1.38 0.42%

Among these substances are the polyols, such as glycerin, sorbitol,maltitol, xylitol, mannitol, etc.

These products can be used with a concentration ranging between 1 and30% in mass in relation to the total mass of the liquid phase.

These preparations being intended, among other things, to be applied tothe oral mucous membrane, flavors as well as sweetening substances canbe added in the bio-adhesive medium.

The flavors can be of natural or synthetic origin same as the sweeteningsubstances.

Besides saccharose conventionally used as a sweetening substance,aspartame, acesulfam, sodium saccharin and sodium cyclamate can beretained as sweetening agents.

Depending on the sweetening substance used, the concentration in themedium can vary from 0.1% to 30% in mass in relation to the total massof the preparation.

The solutions or suspensions thus realized, creating in situ matrixsystems with prolonged release, have viscosities going from 100 mPa and500,000 mPa.

These solutions or suspensions can be packaged:

-   -   in multidosage vials: bottles or tubes    -   in single dose: unidose, Bottle-Pack®, nozzle tubes having        single use    -   in spray: liquid spray or foam formation

Such systems, after application, lead to an action and/or theprogressive release of the active ingredient over a period that can gofrom 1 hour to 48 hours, this kinetic release being little or notdependent on surrounding biological factors. This dissolution kineticcan be of the order of zero or 1 depending on the type of excipientsused to obtain such a release.

Besides the use of these systems within the framework of a prolongedrelease of an active within a cavity, these same systems, in the absenceof any therapeutic molecule, are of interest from a mechanicalstandpoint and, inter alia, regarding the lubrication of the mucousmembranes when these are subject to dryness, such as oral dryness in theoligoptyalism, vaginal dryness, nasal dryness and corneal dryness in thecase of Sjôgren disease.

In fact, these systems, by consequence of the intrinsic lubricatingcharacter of the carrageenans being amplifiable by the incorporation ofmineral or vegetable oils, or surface-active agents, allow maintenanceof a lubricating action over an 8-hour period.

The examples of preparations appearing hereafter are possiblecomposition formulas according to the present invention and they do notlimit it in any way.

EXAMPLE 1 Hydrating Bio-Adhesive Gel for Oligoptyalism

Lambda-carrageenans 5.00% Mint flavor 0.02% Vanilla flavor 0.50%Aspartame 0.01% Demineralized water 94.47%

EXAMPLE 2 Lubricating Bio-Adhesive Gel for Oligoptyalism

Lambda-carrageenans 5.00% Polysorbate 80 2.50% Vegetable oil 2.50% Mintflavor 0.02% Vanilla flavor 0.50% Aspartame 0.01% Demineralized water89.47%

EXAMPLE NUMBER 3 Hydrating Bio-Adhesive Vaginal Gel

Lambda-carrageenans 5.00% Hyaluronic acid 2.50% Paraffin oil 1.00%Auto-emulsionable glycerol monostearate 8.00% Sodium methylparahydroxybenzoate 0.08% Sodium propyl parahydroxybenzoate 0.02% Sodiumhydroxide QS pH 3.5 to 4.5 Demineralized water 73.40% 

EXAMPLE NUMBER 4 Bio-Adhesive Gel for Oral Mycoses

Lambda-carrageenans 2.50% Miconazole 2.00% Pre-gelatinized starch 2.50%Polysorbate 20 2.00% Sodium methyl parahydroxybenzoate 0.08% Sodiumpropyl parahydroxybenzoate 0.02% Ethanol with 96% V/V 1.50%Demineralized water 89.40%

BIBLIOGRAPHY

-   (1) WANG E. S. N and Coll., Corneal absorption reinforcement of    certain mydriatics, J. Pharm. Sci., 1970, 59, 11, p: 1559-1563-   (2) HASS J. S., and Coll., The effect of methylcellulose on response    to solutions of pilocarpine, S. Afr. Med. J., 1975, 49, p: 1259-1265-   (3) GOLDBERG I. and Coll., efficacity and patient acceptance of    pilocarpine gel, Am. J. Ophtalmol. 1979, 15, 3, p: 843-846-   (4) MANDELL A. I., and Coll., Multiclinic evaluation of pilocarpine    gel, Invet. Ophtalmol. Vis. Sci., (Suppl.), avril 1979, p: 165-   (5) MARCH W. F. and Coll., Duration of effect of pilocarpine gel,    Arch. Ophtalmol., 1982, 100, 12, p: 1270-1271-   (6) SCHOENWALD R. D. and Coll., Effect of particle size on ophtalmic    bioavailability of dexamethasone suspension in rabbits, J. Pharm.    Sci., 1980, 69, 4, p: 391-395-   (7) HUI H. W., and Coll. Ocular Delivery of progesterone using a    bioadhesive polymer, Intl. J. Pharma., 26 (1), 203-213, 1985-   (8) NAGAI T., and Coll. Powder Dosage Form of insulin for nasal    administration, J. Contr. Rel., 1(1), 15-22, 1984-   (9) CHU J. S and Coll., viscometric study of polyacrylic acid    Systems and mucoadhesive sustained release gels, Pharmaceutical    research, 9 (11), 1408-12, 1991-   (10) HOSNY E. A, and Coll. Bioavailibility of sustained release    indomethacin suppositories containing Polycarbophil®, Intl. J.    Pharma., 113 (January 16), 209-213, 1995.

1. A viscous liquid composition having reinforced bio-adhesive capacity,for a local application in pasty form with prolonged release of anactive ingredient, characterized in that it includes: (i) a matrix agentallowing the in situ formation of a matrix film with reinforcedbio-adhesive capacity obtained by a reaction of complexation of thematrix agent with one of the components of local secretions or of themucous membrane, (ii) a hydration medium for the matrix agent and (iii)an active ingredient.
 2. A viscous liquid composition according to claim1, characterized in that the matrix agent belongs to the family ofpolysaccharides.
 3. A viscous liquid composition according to claim 2,characterized in that polysaccharide belongs to the family of thecarrageenans.
 4. A viscous liquid composition according to claim 3,characterized in that the carrageenan is selected among the lambda- andthe iota-carrageenans
 5. A viscous liquid composition according to claim3, characterized in that the carrageenan is has a concentration rangingbetween 0.5% and 30% in mass in relation to the total mass of thecomposition.
 6. A viscous liquid composition according to claim 1,characterized in that the hydration medium of the matrix agent is anaqueous solution or hydro-alcoholic.
 7. A viscous liquid compositionaccording to claim 6, characterized in that the hydro-alcoholic phaseincludes ethanol or isopropyl alcohol.
 8. A viscous liquid compositionaccording to claim 6, characterized in that the proportion in alcoholicphase lies between 10% and 90% in mass in relation to the volume totalof the hydrating phase.
 9. A viscous liquid composition according toclaim 1, characterized in that it furthermore includes alkaline oralkaline-earth ions.
 10. A viscous liquid composition according to claim9, characterized in that the proportion of alkaline or alkaline-earthions varies from 0 to 50% in mass in relation to the total mass of thecomposition.
 11. A viscous liquid composition according to claim 9,characterized in that the alkaline or alkaline-earth ions are introducedin the form of hydroxide or a salt of hydrochloric, sulphuric, nitric,phosphoric, citric acid and/or a derivative.
 12. A viscous liquidcomposition according to claim 12, characterized in that the aqueousphase of the hydration medium is a buffer solution.
 13. A viscous liquidcomposition according to claim 12, characterized in that the value ofthe pH of the buffer solution varies from 2 to
 12. 14. A viscous liquidcomposition according to claim 12, characterized in that the buffersolution is constituted by the couples hydrochloric acid/sodiumchloride, hydrochloric acid/potassium phthalate, hydrochloricacid/glycol, citric acid/citrates, citric acid/sodium hydroxide, lacticacid/lactate, monosodium phosphate/disodium phosphate, monopotassiumphosphate/dipotassium phosphate, bicarbonate/carbonate, acid/potassiumdiphthalate, or boric acid/sodium borate.
 15. A viscous liquidcomposition according to claim 1, characterized in that the activeingredient is solubilized in the hydrating phase or in an organicsolvent.
 16. A viscous liquid composition according to claim 15,characterized in that the organic solvent is selected among vegetableoils, mineral oils, natural oils, synthetic oils, conventionallipophilic solvents, hydrophilics and non-toxic hydro-lipophilics.
 17. Aviscous liquid composition according to claim 1, characterized in thatit furthermore includes a surface-active agent
 18. A viscous liquidcomposition according to claim 17, characterized in that thesurface-active agent belongs to the class of ionic, nonionic andamphoteric surface-active agents.
 19. A viscous liquid compositionaccording to claim 17, characterized in that the concentration ofsurface-active agent lies between 0 and 50% in mass in relation to thetotal mass of the excipients.
 20. A viscous liquid composition accordingto claim 1, characterized in that the active ingredient in the solidstate is dispersed in the form of powder of a granulometry rangingbetween 1 μm and 1000 μm.
 21. A viscous liquid composition according toclaim 20, characterized in that the granulometry of the activeingredient lies between 1 μm and 250 μm.
 22. A viscous liquidcomposition according to claim 1, characterized in that it furthermoreincludes starch of rice, of potato, of corn, of manioc, and theirderivatives.
 23. A viscous liquid composition according to claim 22,characterized in that modified starch or the starch concentration liesbetween 0 and 50% in mass in relation to the total mass of thecomposition.
 24. A viscous liquid composition according to claim 1,characterized in that it includes a conservation moistening, coloring,flavoring and/or sweetening agent.
 25. A viscous liquid compositionaccording to claim 24 characterized in that the concentration inpreservatives lies between 0 and 10%.
 26. A viscous liquid compositionaccording to claim 24 characterized in that the concentration inmoistening agents lies between 1 and 30%.
 27. A viscous liquidcomposition according to claim 24, characterized in that theconcentration in dyes lies between 0 and 5%.
 28. A viscous liquidcomposition according to claim 24, characterized in that theconcentration in sweetening substances lies between 0 and 30%.
 29. Aviscous liquid composition according to claim 24, characterized in thatthe sweetening substances are natural or synthetic chosen amongsaccharose, aspartame, acesulfam, sodium cyclamate or sodiumsaccharinate.
 30. A viscous liquid composition according to claim 1characterized in that it presents a viscosity ranging between 100 mPaand 500,000 mPa.
 31. A viscous liquid composition according to claim 1characterized in that the release time of the active ingredient liesbetween 2 and 12 hours for the oral, nasal, and ocular routes.
 32. Aviscous liquid composition according to claim 1 characterized in thatthe release time of the active ingredient is greater than 12 hours forthe vaginal route.
 33. A viscous liquid composition according to claim1, characterized in that the active ingredient belongs to a therapeuticclass selected among: analgesics, anti-inflammatories, antispasmodics,cytotoxics, antibiotics, antifungals, disinfectants, anti-parasitics,hormones, antivirals, anti-migraine agents, antiallergics, respiratoryagents, analeptics, spermicides, anti-hemorrhoidal agents,vasoconstrictors, vasodilators, antipruritics, uterorelaxants,antiglaucoma agents, mydriatics and antiasthmatics.
 34. A viscous liquidcomposition according to claim 1 furthermore including alkaline oralkaline-earth ions of sodium or potassium.